Heart failure occurs when the heart is damaged from diseases such as high blood pressure, a heart attack, poor blood supply to the heart, a defective heart valve, atherosclerosis, rheumatic fever, heart muscle disease and so on. The failing heart becomes inefficient, resulting in fluid retention and shortness of breath, fatigue and exercise intolerance. Heart failure is defined by the symptom complex of dyspnea, fatigue and depressed left ventricular systolic function (ejection fraction<35-40%), and is the ultimate endpoint of all forms of serious heart disease. Despite considerable advances in treatment, heart failure remains associated with high morbidity and mortality.
Heart failure has many causes and pathophysiological origins. For example, aldosterone could have a role in endothelial dysfunction in chronic heart failure and accordingly, mineralocorticoid receptor (MR) is an important drug target particularly for the treatment of heart failure. For example, the aldosterone antagonist spironolactone (also known as ALDACTONE®, PFIZER) is used commonly in the treatment of congestive heart failure. Actually, spironolactone has been shown to be pharmacologically effective and well tolerated, to reduce the overall risks of death, death due to progressive heart failure, and sudden death from cardiac causes, as well as the risk of hospitalization for cardiac causes. Likewise, eplerenone exemplifies another blocker of aldosterone binding at the mineralocorticoid receptor. The therapeutic benefits of eplerenone for the treatment of heart failure have been recently demonstrated in clinical trials.
The neurophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family which has been previously identified as a molecular target of aldosterone through the activation of the mineralocorticoid receptor, a ligand-activated transcription factor. NGAL is able to form a complex with the metalloprotease 9 (MMP9) and increases MMP9 activity by increasing its stability. It was previously showed that tissue expression of NGAL as well as plasma level of NGAL is increased in pathophysiological situations when aldosterone and/or MR is activated in the cardiovascular system and in the metabolic syndrom, both in experimental models and in human patients. Moreover a correlation between the plasma NGAL-MMP9 and plasma aldosterone level has been identified.
Lipocalins are a widely distributed group of proteins which have the ability to bind and transport small hydrophobic molecules and could therefore represent a potential therapeutic target. However, the involvement of NGAL in the pathophysiological effects of aldosterone and MR activation in the heart has not yet been investigated.